The investigation of novel and innovative treatment approaches for long-term management of HIV-infection has intensified due to the growing number of infected individuals worldwide and the constraints of resistance, toxicity and convenience associated with lifelong therapy. Current treatment relies entirely on antiretroviral drugs targeting various stages of the life cycle of HIV, rather than on leveraging the immune system. However, the boosting of HIV-specific immune responses in chronic infection offers a vast potential for synergy with antiretroviral drugs, thereby contributing to durable control of viral replication. The Project Leaders have been collaborating in the past five years to develop a novel immunotherapeutic agent (DermaVir) that delivers plasmid DNA to dendritic cells after topical skin application. Building upon a wealth of promising pre-clinical results that have demonstrated immunological and clinical benefit by DermaVir in chronically infected rhesus macaques in combination with antiretroviral therapy, during the proposed Program, we intend to improve the safety of DermaVir without jeopardizing the efficacy. DermaVir will be tested in non-human primates and finally transitioned to the clinic for the treatment of individuals infected with HIV- 1 and treated with available antiretroviral therapy. In complement to this plan, new immunodiagnostic assays will be optimized and validated for monitoring and perhaps even predicting immune responses in patients undergoing immunomodulatory therapies. The objective of this Program is to offer patients and clinicians an alternative therapeutic approach that diminishes the drawbacks of current antiretroviral treatments. Ultimately, this novel therapeutic vaccine will be ready for further clinical evaluation. The Program is supported by researchers who are innovators in the field, and by a Scientific Advisory Panel consisting of acknowledged leaders in HIV research. It has been designed to ensure a nice continuity and reciprocal flow of valuable information among Projects. This original Program is based on a solid background and on very encouraging preliminary results. Its success will represent a significant step towards the final goal of providing HIV infected patients a broader treatment choice with a new class of immune-based treatment.